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The Link Between Cardiovascular Disease and Dementia

Introduction

Cardiovascular disease (CVD) and dementia often occur
concomitantly, and much has been written about CVD as a risk
factor for dementia -- with some researchers arguing that CVD
can actually cause dementia. Others argue that CVD simply
accelerates or worsens the state of dementia that has already
started to develop. Study outcomes have been at variance, and
the link between these coexisting disorders remains unclear.

Regardless of which disorder appears first -- the heart
disease or the dementia -- or whether one is a precursor to the
other, several groups of researchers have demonstrated
structural changes on cerebral magnetic resonance imaging in
patients with such cardiovascular risk factors as high blood
pressure, high cholesterol, smoking, and diabetes.

Interest in the contributory role of homocysteine, a
sulphur-containing amino acid, in the development of cognitive
dysfunction, has also generated a number of studies, some of
which are discussed in this column, and the potential protective
effect of high-density lipoprotein cholesterol (HDL-C) on
cognition has been explored.

Dementia and Stroke

Studies have reported incidence rates of dementia as high as
25% for stroke survivors, whereby the dementia was directly
attributed to the stroke event.[1-4] An even stronger
correlation between dementia and stroke was reported by Philip
A. Wolf, MD, Boston University School of Medicine (Boston,
Massachusetts), and colleagues,[5] who contended that
patients who have suffered a stroke are twice as likely
as healthy subjects to develop dementia.

Using a nested case-control study, they prospectively
examined risk factors for poststroke dementia in 212
dementia-free subjects selected from the Framingham Study
original cohort who had suffered a first stroke after January
1982, and compared their likelihood of developing dementia
against the dementia risk of 1060 healthy, stroke-free control
subjects who were matched for sex and age. The study performed a
direct comparison of the risk factors for dementia between
subjects who had sustained a previous stroke vs those who had
not to determine whether the same factors that contribute to
dementia risk in people without a previous stroke also
contribute to the elevated risk of cognitive impairment in those
who have suffered a stroke.

Over a 10-year follow-up period, Wolf and colleagues reported
that 19.3% of stroke patients and 11% of controls developed
dementia. The risk was not reduced by adjusting the data for
other possible contributing factors, such as age, sex, education
level, and exposure to individual stroke factors (eg, diabetes
mellitus [DM], atrial fibrillation [AF], hypertension, and
smoking). It was also found that subjects with a specific
genetic pattern of apolipoprotein E (apoE), a blood protein
whose association with CVD has been well established, were 3
times more likely to develop dementia. Patients younger than 80
years of age and high school graduates also had a higher risk
for dementia.

Unlike previous studies which have shown DM to be an
independent predictor of poststroke dementia, in their analysis,
Wolf and colleagues found that none of the individual risk
factors they studied significantly altered the impact of stroke
on the risk of dementia. Thus, they argued, independent risk
factors for stroke may increase the risk of dementia simply by
increasing the risk of clinical stroke.

Monique M.B. Breteler, MD, and colleagues, Erasmus Medical
Center (Rotterdam, The Netherlands),[6] studied the
association between silent brain infarcts and the risk of
dementia and cognitive decline in 1015 subjects who participated
in the prospective Rotterdam Scan Study. Participants ranged in
age from 60-90 years and were free of dementia (as determined by
testing with the Mini-Mental State Examination [MMSE] and the
Geriatric Mental State Schedule) and stroke at baseline. All
subjects had undergone neuropsychological testing and cerebral
magnetic resonance imaging (MRI) between 1995 and 1996, and 739
patients underwent repeat testing (including a second MRI)
between 1999 and 2000. The investigators performed Cox
proportional hazards and multiple linear regression analyses
that were adjusted for age, sex, education level, and the
presence or absence of subcortical atrophy and white-matter
lesions.

By study's end (3697 person-years of follow-up), 30 patients
(3%) had developed dementia and 26 of these cases were diagnosed
as Alzheimer's disease (AD). Patients who had evidence of "silent"
(nonsymptomatic) strokes -- ie, strokes detected
radiographically as silent brain infarcts on their initial MRI
scans -- faced more than double the risk of developing dementia
during the study period as those who experienced strokes that
were preceded by warning signs and symptoms (hazard ratio [HR],
2.26; 95% confidence interval [CI], 1.09-4.70). This remained
true after adjusting for severity of white-matter lesions and
subcortical atrophy. Those with silent strokes also experienced
greater declines in mental function, but this finding was
limited to those who had additional silent strokes during the
study period that caused further damage to brain tissue.

The investigators also analyzed cognitive decline according
to type of infarct and reported that silent thalamic infarcts
were associated with a decline in memory performance, whereas
nonthalamic infarcts were associated with a decline in
psychomotor speed.

When study subjects were subclassified into 4 groups
according to the presence or absence of silent brain infarcts at
baseline and on follow-up MRI, the decline in cognitive function
was only seen in those who had new silent brain infarcts on
follow-up MRI, regardless of whether they had silent infarcts at
baseline. In addition, a greater severity of periventricular
white-matter lesions, believed to result from small-vessel
disease, was associated with an increased risk of dementia.

Breteler and colleagues hypothesized that perhaps an infarct
in a brain already affected by AD-associated abnormalities
further impairs cognition, leading to clinically evident
dementia. Silent brain infarcts may trigger the development of
senile plaques and neurofibrillary tangles or reflect cerebral
vulnerability or a certain vascular risk profile that enhances
AD-associated abnormalities.

They concluded that the presence of silent brain infarcts on
MRI identifies persons at increased risk for dementia, probably
because these patients continue to have additional brain
infarcts, both silent and symptomatic, that decrease their
cognitive function.

Is CVD a Precursor to AD?

Although CVD has been hypothesized by some investigators to
be a precursor to AD, there are others who believe that stroke
may represent an independent injury that simply worsens the
symptoms of AD whose development is already under way.[7]

Seeking to clarify the association between stroke and AD,
Lawrence S. Honig, MD, Gertrude H. Sergievsky Center (New York,
NY), and colleagues[7] studied a cohort of Medicare
recipients from 3 ethnic groups in upper Manhattan, New York
City who did not have dementia at baseline. In this longitudinal
follow-up study conducted from 1992 through 1999, the
investigators calculated incidence rates for AD among those with
and without stroke and performed medical evaluations and
neuropsychological testing.

Of the 1766 study participants, 331 (19%) suffered stroke
during the study, 188 of whom had a history of stroke at
baseline. An additional 143 patients developed stroke during
follow-up and before the onset of dementia. Dementia was
diagnosed in 212 (12%), and Alzheimer's disease was diagnosed in
181 (85%) of those 212 patients by study's end.

The authors reported that the annual incidence of AD was 5.2%
per person-year among individuals with stroke and 4% per
person-year for those without stroke. The hazard ratio for AD in
the stroke patients was 1.6 (95% CI, 1.0-2.4; P = .04)
compared with the group without stroke. In addition, patients
with stroke had earlier onset of AD than those without stroke (onset
at 85.3 vs 88.7 years of age, respectively).

Honig and colleagues also examined the independent influence
of other cardiovascular risk factors on the incidence of AD,
stratifying the analyses by each factor: hypertension, type 2
DM, and heart disease. Of these risk factors, only diabetes was
an independent risk factor for AD in the absence of stroke.
Stroke remained weakly associated with AD in the absence of
these independent variables, but the risk of AD was
significantly increased when stroke was accompanied by the
additional factors of hypertension (relative risk [RR], 2.3; 95%
CI, 1.4-3.6), diabetes (RR, 4.6; 95% CI, 2.2-9.5), or heart
disease (RR, 2.0; 95% CI, 1.2-3.2). Any combination of these 3
risk factors, when added to stroke, led to a significantly
increased risk of AD.

Investigators also found that persons with stroke showed an
earlier onset of AD as compared to those without stroke. Stroke
in the absence of these risk factors remained weakly associated
with AD, but did not achieve statistical significance. Thus, the
investigators concluded that the association between stroke and
AD was highest in those groups who had at least 1 vascular risk
factor concomitantly with stroke. Of all 4 vascular variables
analyzed independently (stroke, hypertension, diabetes, and
heart disease), only stroke by itself was statistically
significantly related to dementia.

The researchers admitted that a limitation of their study is
the possibility that, despite the neurologic and
neuropsychological data suggesting the diagnosis of AD, the
primary neuropathologic abnormalities present in these patients
may have actually been those of vascular dementia, not AD, in
some cases.

"The presence of neuropathologic changes in AD could
predispose some individuals to stroke, perhaps owing to amyloid
angiopathy, brain parenchymal changes, or the secondary
consequences of the presymptomatic disease (eg, dietary or
activity changes)," the study authors wrote. "Whether
stroke is directly involved in the pathogenesis of AD or acts
indirectly as a contributor to the manifestations of AD needs to
be established." The authors believed that stroke
prevention and risk factor management "may have important
implications for AD risk and deserve further investigation."

Risk for Both AD-Associated and Vascular Dementia Higher in
Patients With CVD

Anne Newman, MD, University of Pittsburgh School of Medicine
(Pittsburgh, Pennsylvania), and colleagues[8]
conducted an analysis of patients from the Cardiovascular Health
Study and found that individuals with CVD have a 30% higher risk
of developing both Alzheimer's-associated dementia and vascular
dementia than those without CVD. They also found that the risk
of dementia was highest in patients with peripheral arterial
disease.

In the Cardiovascular Health Study, 5201 people aged >/=
65 years were recruited in 1989-1990 and an additional 687
blacks from 4 US communities were enrolled in 1992-1993; all
subjects underwent physical and cognitive tests annually until
1999.

In their subanalysis, Newman and colleagues evaluated both
traditional risk factors (eg, diabetes, hypertension, and
smoking) and newly identified risk factors (eg, hemostatic
factors, inflammatory markers, exposure to infectious agents,
and genetic determinants) for dementia. They noted that,
although the risk of AD was higher in those with CVD, the higher
risk can be attributed in part to other dementia risk factors
that were concurrently present in these patients.

Comorbid Conditions in Patients With AD Vary According to
Race

Edward Zamrini, MD, University of Alabama at Birmingham, and
colleagues,[9] conducted 2 separate analyses that
compared black patients and white patients with probable AD to
determine whether the black subjects were more predisposed to
certain medical comorbidities than a similar cohort of white
patients and vice versa.

In the first analysis, 166 black patients (41 men and 125
women) and 166 white patients (41 men and 125 women) were
matched according to their compatibility on 4 variables thought
to be important in influencing other medical illnesses: age at
presentation to the clinic, age at AD onset, duration of illness,
and Mini-Mental State Examination (MMSE) scores. In the second
analysis, investigators randomly chose 167 white probable AD
patients for comparison against the 167 previously selected
black patients with probable AD.

Whether groups were deliberately matched or randomly matched,
the outcome was the same: blacks with probable AD had a greater
frequency of hypertension, without associated CVD or heart
disease, than white patients with probable AD (34% of black men
and 29% of black women vs 17% of white men and 20% of white
women; P < .025), whereas white AD patients had a
greater frequency of AF (P < .001) and cancer (P
< .025) than black AD patients. Because these observations
were made in both analyses, the authors concluded that there are
race variations among patients at least with regard to the 3
comorbid medical illnesses occurring in the studied patient
population. However, the authors admit that their Memory
Disorders Clinic patients may not be representative of the
patients residing in the general community.

Early Signs of Cognitive Deterioration in Patients With
Cardiovascular Risk Factors

A small study conducted by Ian Cook, MD and colleagues,[10]
from the University of California at Los Angeles, found that the
progression of certain structural changes in the brain was more
pronounced among subjects with cardiovascular risk factors such
as high blood pressure, high cholesterol, smoking, and diabetes.

The researchers administered a series of tests, including MRI
testing, to a cohort of 29 healthy adults aged >/= 60 years
to evaluate their mental function at the study's outset and then
again 2 to 6 years later. MRI evaluation assessed 2 types of
brain structure changes: atrophy (shrinkage) and white matter
hyperintensities.

Compared with baseline MRI, on the second MRI scan, most
patients showed a progression in brain atrophy and white matter
lesions, and those with cardiovascular risk factors showed
greater white matter changes than those without risk factors did.
Despite the changes in MRI, there was little change in any of
the patients' performance on the mental tests from baseline to
follow-up.

The investigators noted that these structural changes in the
brain can arise from mini-strokes, but healthy older people may
also show similar structural changes, to a lesser degree. Cook
and his colleagues term these subtle early signs of disease
"subclinical structural brain disease" (SSBD). Past
research has tied greater degrees of SSBD to poorer mental
functioning, they noted. Therefore, "the same measures for
preventing heart attack and stroke – exercise, healthy diet,
medications for conditions such as high blood pressure – might
also guard against "more subtle changes" in mental
function," they concluded.

Hypertension and Dementia

High blood pressure may cause changes in blood flow and brain
activity that affect short-term memory, according to a study by
J. Richard Jennings, MD, University of Pittsburgh and Western
Psychiatric Institute (Pittsburgh, Pennsylvania).[11]
Using brain imaging techniques, Dr. Jennings compared blood flow
in the brains of 33 patients with hypertension and 62 patients
with normal blood pressure. Patients ranged in age from 50 to 70
years; all subjects underwent ultrasound and MRI scans of their
carotid arteries, positron emission tomography (while asked a
number of standard memory tests), and a series of neurologic and
psychological function tests. The hypertensive patients were not
taking medication and had no history of stroke. Overall, the
patients with high blood pressure scored slightly worse on tests
of short-term memory, and those with measurable working memory
impairment had less blood flow in the prefrontal and parietal
regions of the brain than the patients with normal blood
pressure.

Impact of Diabetes on Dementia

The frequently reported association between DM and impaired
cognitive function suggests that DM may contribute to AD.
However, few prospective studies have examined the relationship
between DM and incident AD, and those that have focused on this
association have yielded inconsistent results.

Zoe Arvanitakis, MD,Rush Alzheimer's Disease Center (Chicago,
Illinois), and colleagues[12] analyzed data from the
Religious Orders Study, an ongoing longitudinal study of aging
and AD in Catholic nuns, priests, and brothers aged >/= 55
years, to test the hypothesis that DM was associated with an
increased risk of AD and with more rapid cognitive decline. For
a mean of 5.5 years, 824 subjects underwent annual evaluations
that included clinical classification of AD and detailed testing
of cognitive function. Follow-up was conducted for up to 9 years.
Of the 824 participants, 132 (16%) experienced 1 or more strokes
(at the baseline or follow-up evaluation). The association of DM
with AD was not substantially changed after adjusting for stroke
(HR, 1.58; 95% CI, 1.05-2.38). In a subsequent model, the
researchers found no evidence for an interaction between DM and
stroke (P = .68).

Although an association between DM and the pathologic
features of AD has not been established, investigators point out
that recent data raise the possibility of a more direct
relationship between DM and AD. For example, insulin has been
reported to be related to memory function in patients with AD
and to plasma amyloid level and other studies have suggested
potential genetic and cell-based relationships between insulin
and AD.

Cognitive Decline in DM Patients in the Nurses' Health Study

A report from The Nurses' Health Study[13] also
supports the correlation between cognitive decline and diabetes.
This ongoing prospective study of a cohort of more than 120,000
female registered nurses in the United States was designed to
examine the association between DM and poor cognitive
performance or cognitive decline over 2 years of follow-up.
Extensive information on DM and numerous covariates has been
collected and reported via mailed questionnaires administered
biennially since 1976.

From 1995 to 2001, Giancarlo Logroscino, MD, and colleagues,[13]
Harvard School of Public Health (Boston, Massachusetts),
administered baseline telephone cognitive interviews to 18,999
women, aged 70 to 81 years who had not had a stroke and did not
have type 1 diabetes, gestational diabetes, or unconfirmed
diabetes; 2-year follow-up interviews have been completed in 90%
of the participants. Global scores were calculated by averaging
the results of all tests (telephone interview of cognitive
status, verbal fluency, immediate and delayed recalls of the
East Boston memory test, delayed recall of 10-word list, and
digit span backwards).

The investigators identified women who reported that they had
been diagnosed with diabetes before the baseline cognitive
interview. At baseline interview, 1394 women (7.3%) had type 2
diabetes, with a mean duration of 12 years since diagnosis. The
diabetic women had higher incidences of hypertension, high
cholesterol, heart disease, obesity, and depression than the
women without diabetes. On every cognitive test, mean baseline
scores were lower for women with diabetes. After adjusting for
potential confounding factors, the investigators found that
women with diabetes were at 25% to 35% increased odds of having
a poor baseline score on the Telephone Interview of Cognitive
Status (TICS) and the global composite score compared with
nondiabetic women. With longer duration of diabetes, there was a
50% elevation of odds of poor baseline performance. Patients who
reported metabolic complications (ketoacidosis, coma) had a
higher risk of poor performance compared with nondiabetic
subjects. These findings all held true when the researchers
examined cognitive decline over time (for example, on the TICS,
the risk of substantial cognitive decline was 26% higher for
women with DM compared to those without, and this number rose to
a 64% elevation with long duration of diabetes).

The investigators concluded that women with type 2 diabetes
appear at increased odds of poor cognitive performance and
substantial decline over a period of 2 years and that the
increase in risk is especially high for subjects who have
diabetes of longer duration, report metabolic complications, and
do not take antidiabetic medications.

Metabolic Syndrome and its Effect on Stroke Outcomes

Recently reported by P Verhaegen, MD, and colleagues,[14]
Syracuse University (Syracuse, New York), The Berlin Aging Study
was designed to assess the relationship between cognitive
functioning (perceptual speed, memory, fluency, and knowledge)
and cardiovascular and metabolic disease in a sample of elderly
adults (aged </= 70 years), both cross-sectionally (n = 516)
and longitudinally (n = 206), with a 4-year follow-up. After
controlling for certain variables (age, socioeconomic status,
sex, and dementia status), the following 4 diagnoses were
negatively associated with cognition: (1) congestive heart
failure, (2) stroke, (3) coronary heart disease, and (4) DM.
Perceptual speed and fluency were the cognitive factors most
severely curtailed by disease status; memory was affected only
by the presence of diabetes; and knowledge was not affected by
any of the disorders studied. The authors reported that the only
cardiovascular risk factor associated with cognitive performance
in this study was alcohol consumption.

High Homocysteine Levels Contribute to Cognitive Dysfunction

Interest in homocysteine as a risk factor for CVD has mounted
during the last few years. It has been suggested that high
levels of this sulphur-containing amino acid can elevate the
risk of dementia and depression and can confer significant
morbidity and mortality. With the advent of simple assays,
homocysteine measurement has become accepted as a standard and
routine clinical test.[15]

During the past 15 years, it has been thoroughly documented
that moderate elevation of homocysteine levels in serum or
plasma is a strong and independent risk factor for occlusive
arterial disease and venous thrombosis, and is a predictor of
vascular and all-cause mortality. As many as 50% of patients
with stroke and other atherothrombotic diseases have high
homocysteine levels (> 15 micromol/L).[15]

An association between elevated homocysteine levels and
impaired cognitive performance and dementia has also been
documented. Several prospective studies have demonstrated that
folate and/or vitamin B12 status and elevated levels
of homocysteine are predisposing factors for the development of
dementia or contribute to an accelerated rate of progression of
the disease.[15]

Reduction of homocysteine levels has been shown to increase
regional cerebral blood flow and to have a positive impact on
cognitive performance in elderly individuals with mild cognitive
impairment. However, early intervention appears to be crucial,
because severe underlying neuronal and vascular damage is
irreversible (although studies in animals suggest the
possibility of reversibility of neuronal damage). Vitamin
therapy has also been demonstrated to influence the rate of
progression of atherosclerosis and to increase
endothelium-dependent blood flow.[15]

Dr. Ramon Diaz-Arrastia, from University of Texas
Southwestern Medical Center (Dallas, Texas), and colleagues[16]
measured homocysteine levels in blood samples obtained from 235
Parkinson's disease (PD) patients, including 201 patients who
had been treated with levodopa. They observed a statistically
modest increased risk of heart disease in PD patients with
elevated homocysteine. Furthermore, levodopa users in their
study showed significantly higher blood levels of homocysteine
than PD patients who had not taken the drug.

The investigators considered the possibility that low levels
of vitamin B12 and folic acid, which are common
causes of elevated homocysteine levels in the blood, had
contributed to the increased risk of heart disease, but
deficiencies of these vitamins did not explain the elevated
homocysteine levels among patients who had used levodopa in
their study. However, they noted that the retrospective nature
of the study made it impossible to conclude definitively whether
levodopa therapy was responsible for the increased prevalence of
vascular disease. Nevertheless, they do recommend that patients
being treated with levodopa should ask their neurologists to
monitor the level of homocysteine in their blood, particularly
if they are at risk for heart disease.

The authors added that further exploration of this issue is
warranted, in light of the fact that approximately one third of
PD patients develop dementia during the course of their disease,
and therefore it would be important to establish whether
levodopa is partly responsible for increasing that risk.

Plasma Homocysteine Levels: PD Patients vs AD Patients

Diaz-Arrastia, MD, and colleagues[17] also
conducted another study that compared plasma homocysteine levels
in PD patients to those in AD patients in a prospectively
characterized outpatient clinic population. They hypothesized
that the differences between AD patients and controls with
regard to homocysteine levels reported in prior studies may have
become less pronounced because of the recent supplementation of
folate in the food supply and widespread use of multivitamins.
The results of their study indicate that plasma homocysteine
levels increased with age and with carbidopa/levodopa use.

Between February 2001 and June 2002, the researchers obtained
plasma samples from patients in the Memory and Movement
Disorders Units of Massachusetts General Hospital with a
diagnosis of AD (n = 145), mild cognitive impairment (MCI; n =
47), PD (n = 93), and no dementia (n = 88). They also collected
data on age, sex, race, education, family history of AD/dementia,
diagnosis, disease duration, disease severity, and medication
use (eg, use of cholinesterase inhibitors, estrogen, carbidopa/levodopa
use, dopamine agonists, anti-inflammatory agents, antioxidants,
statins, and multivitamins). Results demonstrated that
homocysteine levels were increased in the PD patients compared
with AD patients, those with MCI, and dementia-free control
subjects. The elevated levels within the PD group were primarily
seen in PD cases taking carbidopa/levodopa. Age was associated
with increasing homocysteine levels in all 3 groups. Analysis of
the cohort as a whole demonstrated that individuals taking
multivitamins had lower homocysteine levels compared with those
not taking multivitamins.

High Levels of HDL Cholesterol Not Only Reduce the Risk of
Heart Disease, But Also May Preserve Cognitive Function

The fact that high levels of HDL-C confer a protective
benefit in preventing heart disease is undisputed, but limited
data have been reported examining the effects of HDL-C on
cognitive function.

Nir Barzilai, MD, and colleagues,[18] Albert
Einstein College of Medicine (New York, NY), evaluated HDL
levels and mental function in a group of very elderly patients
(N = 139; age range, 95 to 107 years). They found that blood
levels of HDL correlated significantly with mental function, as
measured by the MMSE. Each decrease in plasma HDL tertile was
associated with a significant decrease in MMSE score.
Furthermore, increased plasma apoliprotein A-I levels and
decreased plasma triglyceride levels were associated with
significantly superior cognitive function. The investigators
concluded that HDL-C may have protective effects on cognition by
contributing to the proper functioning of blood vessels and by
reducing inflammation.

Conclusion

As evidenced by the aforementioned studies, as well as many
others not described here, the relationship between CVD and
dementia continues to be a topic of much interest. A complex and
intricate relationship exists between heart disease and dementia
that warrants continued research, including practical
applications to diagnose and treat the concomitant conditions in
clinical practice. Dementia will become a growing burden to
society as life expectancy increases, so the time to seek
clarification of the relationship between heart disease and
dementia is now.